Silicon-bearing amides

ABSTRACT

Compounds of the formula I: ##STR1## wherein each of R 1 , R 2  and R 3  is, independently, (a) alkyl having from 1 to 22 carbon atoms; or 
     (b) of the formula ##STR2##  in which m is 0, 1 or 2, and each of R&#39; and R&#34; is independently a hydrogen atom, alkyl having from 1 to 3 carbon atoms, alkoxy having from 1 to 3 carbon atoms, or halo having an atomic weight of from about 19 to 127; and R is of an aralkyl-, phenyl- tryptophanyl- or benzocycloalkyl-type, are obtained by hydrogenating corresponding α-β ethylenically-unsaturated analogs (II), which in turn are obtained by hydrogenating corresponding α-β acetylenically-unsaturated analogs. Compounds I and II are useful as anti-atheroslerotic agents.

This is a division of application Ser. No. 215,414, filed Dec. 11, 1980,which in turn is a continuation-in-part of application Ser. No. 80,424,filed Oct. 1, 1979, now U.S. Pat. No. 4,420,475, which in turn is acontinuation-in-part of application Ser. No. 074,002, filed Sept. 10,1979, now abandoned.

This invention relates to silicon-bearing amides, and more particularlyto a method of preparing a class of silicon-bearing amides, a subclassthereof which is novel, novel intermediates in preparation of said classof amides, and the pharmaceutical use of said novel compounds andcertain intermediates, as well as pharmaceutical compositions comprisingsaid pharmaceutically useful novel compounds and intermediates.

The final compounds (I) which are obtainable by the process of thisinvention may conveniently be represented by the formula I: ##STR3##wherein each of R¹, R² and R³ is, independently,

(a) alkyl having from 1 to 22 carbon atoms; or

(b) of the formula ##STR4## in which m is 0, 1 or 2, and each of R' andR" is independently a hydrogen atom, alkyl having from 1 to 3 carbonatoms, alkoxy having from 1 to 3 carbon atoms, or halo having an atomicweight of from about 19 to 127; and R is of type (a) an aralkyl-typeradical of the structure

(a) ##STR5## wherein g is 0, 1 or 2;

R^(a) is a hydrogen atom, halo having an atomic weight of from about 19to 127, alkoxy having from 1 to 4 carbon atoms, or alkyl having from 1to 4 carbon atoms, or trifluoromethyl;

R^(b) is a hydrogen atom, alkyl having from 1 to 3 carbon atoms, alkoxyhaving from 1 to 3 carbon atoms, or halo having an atomic weight of fromabout 19 to 36; and

R^(c) is subtype (i) a hydrogen atom; subtype (ii) a radical of thestructure

(ii) ##STR6## in which

p is 0, 1 or 2, and

y is a hydrogen atom, halo having an atomic weight of from about 19 to127, alkoxy having from 1 to 4 carbon atoms, or alkyl having from 1 to 4carbon atoms; and

y' is a hydrogen atom, alkoxy having from 1 to 3 carbon atoms, alkylhaving from 1 to 3 carbon atoms, or halo having an atomic weight of fromabout 19 to 36; or

subtype (iii) alkyl having from 1 to 8 carbon atoms; or R is of type (b)a phenyl-type radical of the structure

(b) ##STR7## in which

R^(b) is as defined above, and

R^(o) is a hydrogen atom, halo having an atomic weight of from about 19to 127, ie. alkoxy having from 1 to 4 carbon atoms, or alkyl having from1 to 4 carbon atoms; or

R^(o) is a radical of the structure R^(f) : ##STR8## in which

D is --CH₂ -- or --O--;

f is 0 or 1; and

W is a hydrogen atom, halo having an atomic weight of from about 19 to80, alkoxy having from 1 to 3 carbon atoms, or alkyl having from 1 to 3carbon atoms; or R is of type (c) an indolyl radical of the structure:

(c) ##STR9## wherein

R^(b) is as defined above;

R⁴ is hydrogen; an equivalent of a cation which results in the formationof a salt which is pharmaceutically acceptable; alkyl having from 1 to 8carbon atoms; or benzyl;

R⁵ is a hydrogen atom, alkyl having from 1 to 8 carbon atoms or benzyl;or

R is (d) a benzocycloalkyl nucleus of the structure:

(d) ##STR10## wherein

y and y' are as defined above; and

j is a whole integer of from 1 to 4.

In the above-presented definition of Compounds I, halo having an atomicweight of from about 19 to 36, includes fluoro and chloro; halo havingan atomic weight of from about 19 to 80 includes fluoro, chloro andbromo; while halo having an atomic weight of from about 19 to 127includes fluoro, chloro, bromo and iodo. Exemplary of alkyl or alkoxyhaving from 1 to 3 or 1 to 4 carbon atoms is methyl, or methoxy andethoxy. Unless otherwise indicated, alkyl and alkoxy may be branched orunbranched.

Compounds I", i.e. compounds I as defined above in which at least one ofR¹, R² and R³ is of type (b), are novel and constitute an embodiment ofthis invention. Those Compounds I which are not part of this inventionare intended to be excluded by the above-presented proviso, althoughtheir preparation by the processes described herein constituteembodiments of this invention. Those compounds I which are excluded aredescribed and claimed in pending application of Sandor Barcza, Ser. No.199,982 filed Oct. 23, 1980.

Particular embodiments of this invention are Compounds I (includingCompounds I") and intermediates thereof in which not more than two ofR¹, R² and R³ are of type (b). Additional sub-classes are thosecompounds in which two of R¹, R² and R³ are the same, and those in whichR² and R³ are alkyl, having from 1 to 3 carbon atoms, e.g. methyl, andR¹ is alkyl having from 8 to 14 carbon atoms, e.g. n-decyl. Preferredcompounds I' are those in which R¹ =R² =type (b) in which m=0 or 1,particularly 0, and R³ =type (a). Preferred compounds I are also thosein which R is of type (a); particularly where R is 1-phenyl2-(p-tolyl)-ethyl.

Further preferred forms of Compounds I when R is of type (a) or (b) andR^(o) is not R^(f), are that it is preferred that when R^(a), R^(o) or yis other than a hydrogen atom and R^(b) (or y') is a hydrogen atom, thatR^(o), or R^(a), or y be located at the 4-position; and that when R^(b)(or y') is also other than a hydrogen atom that R^(a) or R^(o) and R^(b)(or y and y') are the same, and it is additionally preferred that theybe located at the 2- and 4-positions of the phenyl ring. When R is oftype (a) where g=1, and R^(c) is of type (ii) where p=0, then R can bean 1-(phenyl)-2-(p-methylphenyl)ethyl radical, and when R^(c) is of type(ii) where p=1, then R can be an 1-(benzyl)-2(phenyl)ethyl radical.

With particular respect to the substituent R^(o) when it is a radicalR^(f), it will be appreciated that when D=CH₂ and f=1, then the radicalR^(f) is of the benzyl type. When D=oxygen and f=1, then the radicalR^(f) is of the phenoxy-type. When f=zero, then the radical R^(f) is ofthe phenyl-type. Hence, when R is of type (b) and R^(o) is of type R^(f)where f=zero, then R can be a biphenylyl radical. The radical R^(f) ispreferably at the para-position. When W is other than a hydrogen atom,it is preferably at the para-position.

With respect to R, when it is of type (c), it is preferred that whenR^(b) is other than a hydrogen atom, it be located at the 5-position ofthe indole nucleus. It is also preferred that when R⁴ is alkyl, it isunbranched, particularly ethyl.

Compounds I in which R is of type (c) may be regarded as falling intoone of two subclasses, ie Compounds Ic where R⁴ is hydrogen or a cation;and Ic' where R⁴ is alkyl or benzyl. Compounds Ic' are preferred.Compounds Ic may be prepared directly or by hydrolyzing a correspondingcompound Ic'.

A generally applicable and convenient method of carrying out thehydrolysis is to treat an appropriate Compound Ic' with a dilute aqueoussolution of a water-soluble alkali hydroxide, eg. sodium or potassiumhydroxide (5 to 15%) at moderate temperatures eg. 20° to 100° C.,preferably in the presence of a water-miscible co-solvent, such as alower alkanol, eg ethanol. Such hydrolysis yields a compound Ic in whichR⁴ is the cation corresponding to the respective alkali metal hydroxideemployed. Such compound may be recovered as such, or the reactionmixture neutralized and the free acid form of a Compound Ic (where R⁴=H) recovered.

In those instances where a particular Compound Ic' ester is acid-labile,rather than base-labile, eg where R⁴ is t-butyl, an analogous procedureto that described above, can be followed except using dilutehydrochloric or sulfuric acid in place of the alkali metal hydroxide, inwhich case a Compound Ic in free acid form, rather than thecorresponding salt of the alkali metal hydroxide is obtained. As is wellunderstood, free acid and salt forms are inter-convertable in accordancewith well known techniques.

With respect to R when it is of type (d) it is preferred that when y isother than a hydrogen atom, that it be located at a carbon atom ortho tothe ring junction; and that when y' is also other than a hydrogen, it ispreferred that it be the same as y, and it is additionally preferredthat it be in para-relationship to y'. It is additionally preferred thatthe amide group be linked to a carbon of the cycloalkyl moiety which isdirectly bonded to a ring junction carbon. It is also preferred that jbe 1, ie, that the benzocycloalkyl nucleus be indanyl, and particularly1-indanyl.

In the above-presented definitions, when R^(o), R¹ or y is halo, it ispreferably fluoro or chloro, and particularly chloro; and when R² or y'is halo it is preferably chloro.

Those compounds I which are other than Ic are defined hereinafter as I'.Hereinafter, R' is the same as R, but when it is of type (c), then R⁴ isalkyl or benzyl, ie it is other than H or a cation. Intermediates ofCompounds I are compounds II and III, hereinafter described. Analogousto Compound I', those compounds II and III in which R is R' aredesignated as II' and III', respectively, and corresponding analogs ofIc' and Ic; are IIc' and IIc; and IIIc' and IIIc. Hence, just asI=I'+Ic; II=II'+IIc; and III=III'+IIIc.

The above-described compounds I are obtainable by reduction ofcorresponding ethylenically unsaturated silicon-bearing compounds offormula II: ##STR11## in which R¹, R², R³, and R are as defined above(process a). Compounds I and II have pharmaceutical activity as isdescribed hereinafter under the heading "Statement of Utility".

The above described compounds II are obtainable by reduction ofcorresponding alkynyl Compounds (III): ##STR12## in which R¹, R², R³ andR are as defined above (process b).

Process (b) may be accomplished by means conventionally employed inconverting an alkynyl-bearing compound to its correspondingalkenyl-analog. A convenient method of carrying out process (b) is bytreating a compound III with hydrogen in the presence of an appropriatecatalyst such as palladium on calcium carbonate (eg 5%), or rhodium,platinum or platinum oxide, on such "controlling" porous supports ascalcium carbonate, barium sulfate and the like, in an inert medium, eg alower alkanol such as ethanol, lower fatty acids and esters, such asacetic acid and ethyl acetate, hydrocarbons, such as benzene or tolueneor a cyclic ether such as tetrahydrofuran (THF), at moderatetemperatures, for example from about 10° to 80° C. particularly at fromabout 20° to 30° C., at moderate pressures, eg from about 15 to 100 psi(over atmospheric pressure), eg at 15 psi (over at.).

If desired Compounds III may be converted to their correspondingCompounds I (without recovery of any Compounds II formed during theprocess, ie process a') by means conventionally employed in reducing analkynyl compound to its corresponding alkyl analog.

Processes (a) and (a') may be accomplished, for example, byhydrogenating under pressures of eg, from about 15 psi to about 100 psi(all over atmospheric pressure), eg 50 psi in the presence of a catalystsuch as platinum oxide or other hydrogenation catalysts mentioned inconnection with process (b) above, or an active supports, such ascharcoal, in an inert medium, such as ethyl acetate, or such media asmentioned in connection with the discussion of process (b) above, and atmoderate temperatures, eg 10° to 100° C., particularly at from about 20°to 30° C.

It will be appreciated that by selection of such factors as catalyst,pressure of hydrogen, temperature, and reaction time, optimum yields ofthe desired compounds I or II may be obtained from correspondingCompounds III, since "total" hydrogenation of the starting alkynylcompound (III) will result in the formation of a corresponding CompoundI, while controlled hydrogenation will give predominantly a Compound II.Accordingly, compounds III' ie compounds III in which R is R', willyield corresponding Compounds I' or II'.

Compounds III' are obtainable by reaction of a correspondingorgano-metallo Compound of the formula IV: ##STR13## in which R' is asdefined above and M is an equivalent of an active metal eg an alkalimetal or a magnesium halide with a halo-silane of the formula V:##STR14## in which R¹, R² and R³ are as defined, and Z is halo having anatomic weight of from about 19 to 127, ie fluoro, chloro, bromo or iodo,preferably chloro, (process c), to form an adduct which is thenhydrolyzed (process c').

Process (c) is carried out under essentially anhydrous conditions, egunder an atmosphere of inert gas such as dry nitrogen, as areconventionally observed in carrying out Grignard-type reactions, atmoderate temperatures, eg -40° to 0° C., in an aprotic medium, eg anether such as tetrahydrofuran, dimethoxyethane, or a hydrocarbon such asbenzene or toluene, which yields an adduct which corresponds to acompound III but in which the "amido" nitrogen atom bears an M-unit (Mbeing as defined above) or a hydrolyzable silyl group corresponding toV, where an excess thereof is used.

The hydrolysis step (process c') may be accomplished in the conventionalmanner for hydrolyzing a Grignard-type adduct, by treatment with wateror a dilute aqueous solution of a salt of acid, eg, saturated aqueousammonium chloride, at moderate temperatures eg from about 5° to 90° C.,preferably at from about 20° to 30° C.

The above-described Compounds IV are obtainable by treatment of acorresponding propiolamide of the formula VI: ##STR15## in which R' isas defined above, with a M-contributing agent (process d).

Process (d) may be accomplished in the conventional manner for formingorgano-metallic reagents by replacing acidic hydrogen atoms of anorganic compound with active metal atoms. For example Compounds IV maybe obtained by treating the free form of a Compound VI with at least 2equivalents of M-contributing agent (VII) (preferably at least 3equivalents where R' is of type (c) at reduced temperatures, for exampleCompounds VI and VII may be combined at about -78° to -20° C., eg -60°C., and held at low temperatures with agitation while they are reacting,eg at about -40° to 0° C., eg -20° C., in an aprotic medium, eg anether, such as THF, dimethoxyethane, or a hydrocarbon, such as hexane,benzene or toluene. Since Compounds IV are decomposed by moisture, it isconvenient to employ them directly in Process (c) without recovery,which could involve exposure to moist air, or to maintain them in aconventional stabilizing medium, such as the moisture-free inert aproticmedia suitable for use in process (d).

In the M-contributing agents, (Compounds VII), M is an equivalent of anactive metal, or a magnesium halide. Active metals include the alkalimetals, ie lithium, sodium and potassium, lithium being preferred, whilethe halo portions of the magnesium halide may be chloro or bromo. Aconvenient lithium-contributing agent is lithium diisopropylamide (LDA)which may be prepared by reacting n-butyl lithium dissolved in an inerthydrocarbon, such as hexane, with an equivalent of diisopropylaminedissolved in an aprotic solvent, eg THF, at reduced temperatures such asat about -78° to +25° C., eg at -30° C., under essentially anhydrousconditions. It is convenient to prepare the reagent (VII) and use it insitu in process (d).

The above-described propiolamides (VI) are obtainable by amidation ofpropiolic acid, or an active derivative thereof, with an R'-bearingprimary amine of the formula IX:

    H.sub.2 N--R'                                              IX

in which R' is as defined above. A convenient method of carrying outsuch an amidation reaction is by reacting a mixed anhydride of propiolicacid of the formula VIII: ##STR16## in which R⁶ is lower alkyl havingfrom 1 to 6 carbon atoms, eg ethyl, with a compound IX (process e). Thedesired compound VIII may be prepared and used in situ, by treatingpropiolic acid with an equivalent amount (or slight excess) of anon-nucleophilic base, eg an alkali hydride, such as lithium hydride orsodium hydride, or triethylamine, under essentially anhydrousconditions, in an aprotic medium, eg an ether, such as THF, ordimethoxyethane, a hydrocarbon such as benzene or toluene, or ahalogenated hdyrocarbon such as methylene chloride or chloroform, atmoderate temperatures eg from about 0° to 30° C., preferably from about20° to 25° C., then slowly introducing into the reaction mixture achloroformate of the formula X: ##STR17## in which R⁶ is as definedabove, (process e'), at reduced temperatures, eg from about -20° to -5°C., preferably below 10° C., in an aprotic medium such as was used inpreparing the reaction mixture, under essentially anhydrous conditions.

The desired amido compound (VI) may be conveniently obtained by slowlyadding an amine (IX) to a mixed anhydride, in such aprotic media asdescribed in connection with the preparation of the mixed anhydride (egin situ) at reduced temperatures, eg from about -25° to 0° C.,preferably at from about -15° to 0° C.

The above-described series of reactions may conveniently be representedby Reaction Scheme A below, in which R', R¹, R², R³, R⁶, Z and M are asdefined above to obtain compounds I', II' and III'. However it will beappreciated that in preparing compounds I by the above-describedmethods, that in those processes which involve hydrogenation, thatpreliminarily thereto, an unsaturated substrate (II' or III'), in whichR⁴ of the amido moiety is alkyl or benzyl may be hydrolyzed by adaptingthe above-described procedure for converting a compound Ic' to acompound Ic. Hence a Compound III' (or II') in which R⁴ is alkyl orbenzyl may be converted to its corresponding Compound III (or II) inwhich R⁴ is H or a cation, and then hydrogenated to obtain the desiredCompound II or I. ##STR18##

Various modifications of the above-described procedure for obtainingCompounds I and II are possible, and may be conveniently practiced,depending upon such factors as relative availability of startingmaterials and reagents, scale of production, ease of handling etc. Forexample, to obtain Compounds III, one may prepare silicon-bearing estersof the formula XI ##STR19## in which R¹, R², R³ and R⁶ are as definedabove, and react such ester (or free acid form thereof), with an aminocompound of the formula IXc:

    H.sub.2 NR                                                 IXc

in which R is as defined above, under conditions conventionally employedin preparing amides.

Alternatively, the acetylenically unsaturated position of an estercompound (XI) as defined above, may be hydrogenated fully to obtain anester of the formula XII ##STR20## in which R¹, R², R³ and R⁶ are asdefined above, and then reacted with an amine IXc to obtain thecorresponding final compound I; or partially hydrogenated to obtain aethylenically unsaturated ester XIII: ##STR21## in which R¹, R², R³ andR⁶ are as defined above, which upon reaction with an amine IXc willyield the corresponding compound II.

An alternative method of preparing Compounds III is by reacting underessentially anhydrous conditions an active metal salt form of propiolicacid of the formula XIV: ##STR22## in which M^(a) is an equivalent ofactive metal or magnesium halide, with a suitable tri-substituted halosilane (V, as described above) in connection with process (c), in anaprotic medium, at moderate temperatures, eg. 0° to 40°, preferably at20° to 30° C. The same media may be used as mentioned in connection withprocess (c) to obtain a tri-substituted-silyl-alkynoic acid compound ofthe formula XV: ##STR23## in which R¹, R² and R³ are as defined above,which is then reacted with a suitable amine IXc to obtain thecorresponding compound III.

If desired, an ester form of propiolic acid may be employed in place ofcompound XIV, ie of the formula XIV': ##STR24## in which M^(a) and R⁶are as defined above.

The above-described alternative procedures may be convenientlyrepresented by Reaction Scheme B, below, in which R¹, R², R³, R⁶, R, Z,and M^(a) are as defined above. ##STR25##

Recovery of the intermediates and products obtained by theabove-described procedures may be effected by conventional techniques,such as crystallization, precipitation, vacuum distillation, andchromatographic techniques such as column or thin layer chromatographyand the like.

It will be understood that many compounds of this invention, eg I, IIand III, may exist in the form of stereoisomers, eg optically activeisomers, ie enantiomers, which can be prepared from respectivestereoisomers, eg optically active compounds IX or separated andrecovered by conventional techniques, eg, resolution and such isomericforms are also included within the scope of this invention.

Many of the reagents and compounds involved in the above-describedprocedures are known, eg propiolic acid and compounds V and IX, and maybe obtained commercially or may be prepared by methods described in theliterature, while those compounds not specifically described in theliterature may be prepared by analogous methods from known startingmaterials.

STATEMENT OF UTILITY

The compounds I and II of this invention are useful as pharmaceuticalagents in animals. In particular, the compounds I and II are useful incontrolling the cholesterol ester content of mammalian arterial wallsand are therefore particularly indicated for use as antiatheroscleroticagents, i.e., agents useful in the prophylatic treatment ofatherosclerois and in the controlling of atherosclerotic conditions dueto cholesterol ester accumulation in the arterial walls. Such ability ofthe compounds I and II is indicated by known test procedures in whichthe total cholesterol ester content of cultured cells is shown to bereduced by a test compound, as compared to untreated cells, and carriedout, for example, by the following procedures:

(A) Cell Culture

Rnesus monkey smooth muscle cells (from the arterial, e.g., aorta, wall)obtained by the method of K. Fisher-Dzoga et al. [Experimental andMolecular Pathology 18, 162-176 (1973)] are routinely grown in 75 cm²tissue culture flasks using Minimum Essential Medium (Eagle)supplemented with 10% fetal bovine serum. For testing a 75 cm² flaskwith a near confluent cell growth is selected. The cells are removedfrom the flask surface by mild enzymatic treatment with pronase. Aftercentrifugation and decanting the enzyme solution, the cell pellet isresuspended in an appropriate volume of media for seeding the desirednumber of 60 mm tissue culture dishes. Five (5) ml. of the diluted cellsuspension are pipetted into each dish. After seeding, the dishes arelabelled with the cell type, date and flask number of origin andincubated at 37° C. in approximately 5% CO₂ atmosphere in a highhumidity incubator. When the cultures are confluent, the actual drugtesting is begun. Test compounds are routinely solubilized in 100%ethanol. An equivalent amount of ethanol is added to control groups aswell. The tissue culture dishes are randomly divided into groups. To onegroup, hyperlipemic rabbit serum (HRS) is added at 5% by volume(control). To the remaining groups, 5% HRS and 0.1 to 1 mg. per 100 ml.of media of the test compound are added. The dishes are returned to theincubator for an additional 24 hours. All operations through to thefinal incubation are performed using sterile technique in a laminar flowhood. After the incubation period, the dishes are microscopicallyobserved with the Zeiss Axiomat with phase contrast optics and theconditions of the cultures are recorded; especially in regard to thesize, number and configuration of cytoplasmic inclusions and to cellularmorphology. The media is removed from the cultures and 0.9% sodiumchloride solution is added. The cells are removed from the flasks withthe aid of a rubber policeman and transferred to a conical granuatedcentrifuge tube. The cells are washed three times by suspending in anisotonic salt solution, centrifuging at 800×g. for 10 minutes andaspirating the supernatant fluid.

(B) Cell Extraction Procedure

An appropriate volume of isopropyl alcohol (about 1 ml/mg. protein) isthen added to the cell pellet and the sample sonicated with a microprobe (140×3 mm.) for 10 seconds with a "LO" setting of 50 on a BronwellBiosonik IV. After contrifugation for 15 minutes at 800×g., the clearsupernatant is decanted and an aliquot taken for cholesterol analysis.

The residue is dissolved in 0.1N sodium hydroxide and an aliquot takenfor protein determination by the method of Lowry, et al. (J. Biol. Chem.193, 265; 1951).

(C) Assay

Free cholesterol: The isopropyl alcoholic solutions of standards,samples and blank (isopropyl alcohol alone) are treated in a similarmanner. An aliquot of 0.4 ml. of free agent (Reagent A, Table 1 below)is added to a 10×75 mm. disposable glass test tube to which 20 μl. ofthe isopropyl alcoholic solution is added and mixed. After standing atroom temperature for approximately 5 minutes, 0.8 ml. of 0.5N sodiumhydroxide (Reagent C, Table 1) is added and mixed. The fluorescence ismeasured with an Aminco-Bowman spectrophotofluorometer with anexcitation wavelength of 325 nm and emission wavelength of 415 nm. A 1cm. light path cuvette is used with a xenon lamp, an IP28photomultiplier tube and 2 mm slits.

Total cholesterol: The same procedure described above for freecholesterol is followed for total cholesterol except that the totalreagent (Reagent B, Table 1) is used instead and the samples areincubated for 20 minutes at 37° C. before the addition of the 0.5Nsodium hydroxide solution (Reagent C, Table 1).

Alternatively, the assay for cholesterol, i.e., Step C (above) obtainedfrom Steps A and B, may be carried out by the method of Ishikawa et al.(J. Lipid Res. 15, 286; 1974).

The amount of cholesterol ester is found by subtracting the amount offree cholesterol from the total cholesterol content of the cellsdetermined by the assay. A finding of a lower amount of cholesterolester in the group of cells to which test compound was added, ascompared to the control group (untreated) shows that the test compoundis active in reducing the cholesterol ester in the cells.

                  TABLE 1                                                         ______________________________________                                        Composition of Reagents for                                                   Cholesterol Determination                                                     ______________________________________                                        A.     Free Cholesterol Reagent                                                      Sodium phosphate buffer pH 7.0                                                                     0.5     M                                                Cholesterol oxidase  .08     U/ml                                             Horseradish peroxidase                                                                             30.00   U/ml                                             p-Hydroxyphenylacetic acid                                                                         .10     mg/ml                                     B.     Total Cholesterol Reagent                                                     Sodium phosphate buffer pH 7.0                                                                     .05     M                                                Cholesterol ester hydrolase                                                                        .08     U/ml                                             Cholesterol oxidase  .08     U/ml                                             Horseradish peroxidase                                                                             30.00   U/ml                                             Sodium taurocholate  5.00    mM                                               Triton X 100         .015%                                                    p-Hydroxphenylacetic acid                                                                          .15     mg/ml                                     C.     Sodium Hydroxide Solution                                                                          .5      N                                         ______________________________________                                    

Following the above-described test method, comparative test results werecarried out and are reported in Tables 2 and 3 below, in which monkeyaortic smooth muscle cells were originally obtained from Dr. K.Fisher-Dzoga: Univ. of Chicago, the test compound (Compound A) is(±)-4,4-dimethyl-4-sila-tetradecanoyl-1'-phenyl-2'-p-tolyl-ethylamide ofExample 6d administered at 1 μg/ml of media.

                  TABLE 2                                                         ______________________________________                                        Comparative Test                                                              Protein     Cholesterol (μg/mg cell protein)                                                               Percent                                       mg/                    Ester        From                                      Compound                                                                              culture Total   Free Amount Mean  Control                             ______________________________________                                        None    0.378   83.41   38.78                                                                              44.63                                            (Control                                                                              0.442   75.41   35.43                                                                              39.98  42.0  --                                  "       0.376   79.07   37.66                                                                              41.41                                            A       0.432   47.99   44.93                                                                              3.06   3.5   92*↓                         "       0.440   51.20   47.52                                                                              3.68                                             "       0.440   51.20   47.52                                                                              3.68                                             ______________________________________                                         *significant at p less than 0.01                                         

                  TABLE 3                                                         ______________________________________                                        Protein     Cholesterol (μg/mg cell protein                                                                Percent                                       mg/                    Ester        From                                      Compound                                                                              culture Total   Free Amount Mean  Control                             ______________________________________                                        None                                                                          Control 0.364   56.18   38.52                                                                              17.66                                            "       0.364   60.30   37.82                                                                              22.47  20.2  --                                  "       0.330   59.24   38.70                                                                              20.54                                            A       0.436   44.15   39.61                                                                              4.54   5.4   73*↓                         "       0.420   42.98   37.55                                                                              5.43                                             "       0.524   42.46   36.30                                                                              6.16                                             ______________________________________                                         *significant at p less than 0.01                                         

The compounds of the formula I are also indicated as useful asatherosclerotic agents in tests involving oral administration to rabbitsat a dose of 15 to 50 mg/kg of the test compound per day for 9 weeks inconjunction with a high cholesterol diet resulting in, compared tocontrols, a reduction in cholesterol and cholesterol ester serum levels,as well as lessened formation or absence of arterial wall plaques.

When the compounds are employed for the above utility, they may becombined with one or more pharmaceutically acceptable carriers, e.g.,solvents, diluents and the like, and may be administered orally in suchforms as tablets, capsules, dispersible powders, granules, suspensionscontaining, for example, from about 0.5 to 5% of suspending agent,syrups containing, for example, from about 20 to 50% ethanol, and thelike, or parenterally in the form of sterile injectable solutions orsuspensions containing from about 0.5 to 5% suspending agent in anisotonic medium. These pharmaceutical preparations may contain, forexample, from about 0.5% up to about 90% of the active ingredient incombination with the carrier, more usually between 5% and 60% by weight.

The antiatherosclerotic effective dosage of active ingredient employedfor the reduction of cholesterol ester content in the arterial walls ofa mammal may vary depending on the particular compound employed, themode of administration and the severity of the condition being treated.However, in general, satisfactory results are obtained when thecompounds I and II are administered at a daily dosage of from about 0.2milligrams to about 500 milligrams per kilogram of animal body weight,preferably given in divided doses two to four times a day, or insustained release form. For most large mammals, the total daily dosageis from about 10 milligrams to about 5,000 milligrams. Dosage formssuitable for internal use comprise from about 2.5 to 2500 milligrams ofthe active compound in intimate admixture with a solid or liquidpharmaceutically acceptable carrier. Solid carriers include starch,lactose and kaolin, while liquid carriers include sterile water,polyethylene glycols and edible oils such as corn, peanut and sesameoils, as are appropriate to the nature of the active ingredient and theparticular form of administration desired. Adjuvants customarilyemployed in the preparation of pharmaceutical compositions may beadvantageously included, such as flavoring agents, coloring agents,preserving agents, and antioxidants, e.g., vitamin E, ascorbic acid, BHTand BHA.

The preferred pharmaceutical compositions from the stand-point of easeof preparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. When water is acarrier, it is preferred that a suspending agent be present.

Representative formulations for administration orally three times a dayprior to feeding the treatment of atherosclerosis are gelatin capsulesprepared by conventional techniques to contain the following:

    ______________________________________                                        Ingredient             Weight (in mg.)                                        ______________________________________                                        (±)-4,4-dimethyl-4-sila-tetradecanoyl-                                                            250                                                    1'-phenyl-2'-p-tolyl-ethylamide                                               (±)-4,4-diphenyl-4-sila-n-octanoyl-                                                                       250                                            1'-phenyl-2'-p-tolyl-ethylamide                                               corn oil               500     500                                            ______________________________________                                    

As is the present understanding in the art, controlling the totalcholesterol content of an arterial wall by inhibiting the accumulationthereof by reducing the cholesterol ester content thereof,advantageously inhibits the formation of plaques in the arterial wall.

While the inventor does not wish to be bound by any proposed theory ofthe mechanism of the action of Compounds I, it has been observed intests on the compound of Example 6d using the Zilversmit Dual IsotopeMethod* that the compounds substantially reduce absorption ofcholesterol from the gastro-intestinal system of the host, ie at theintestinal wall, possibly by action involving the Acyl Coenzyme Acholesterol acyl transferase (ACAT) enzyme, resulting in a markedreduction of cholesterol intake into the blood of the host, as well as areduction in the cholesterol content (in free and as ester form) ofsmooth muscle cells of the host, eg arterial walls, such as those of theaorta and coronary arteries.

The following examples of the preparation of intermediates and compoundsI and II of the invention are illustrative of the invention. Alltemperatures are centigrade (°C.) and room temperature is 20° to 30° C.unless indicated otherwise. It will be understood that the Compounds I,II and III hereinafter described are obtained as mixtures ofsterioisomers, unless indicated otherwise.

EXAMPLE 14,4-Diphenyl-4-sila-pentanoyl-(1'-phenyl-2'-p-tolyl)-ethylamide##STR26## Step A: N-[(1'-phenyl-2'-p-tolyl)-ethyl]-propiolamide##STR27##

95 mg of lithium hydride are added to a solution of 850 mg propiolicacid in 15 ml of freshly distilled THF, portion-wise, over a period ofabout 45 min., with cooling to avoiding heating over room temperature(hydrogen evolves). The resulting mixture is then cooled to about -10°,and a solution of 1.3 g of ethyl chloroformate in 3 ml of dry THF isadded drop-wise with stirring, while maintaining the temperature below-10°. The resulting mixture is then stirred for 2 hrs. at about -15°. Asolution of 2.5 g of (1-phenyl 2-p-tolyl)-ethylamine in 5 ml of dry THFis then added dropwise at from -15° to 0°, with stirring. The mixture isthen stirred at room temperature for 2 hours.

The reaction mixture is concentrated by evaporation in vacuo (solventstripped) to obtain a residue, which is taken up in methylene chlorideand is washed first with dilute aqueous sodium bicarbonate, then withdilute hydrochloric acid, then dried over anh. sodium sulfate, andconcentrated in vacuo to obtain crude product. The crude product of thisstep is refined by crystallizing from diethyl ether m.p. 152°-155° C.

Step B:4,4-Diphenyl-4-sila-pent-2-ynoyl-(1'-phenyl-2'-p-tolyl)-ethylamide (aCompound III) ##STR28##

In a vessel, under an atmosphere of dry nitrogen at -30° 460 mg ofn-butyl lithium in 10 ml of dry hexane is added to 300 mg ofdiisopropylamine in 15 ml of dry THF. The mixture stirred for 15 min.,then cooled to -60°. A solution of 600 mg of[(1'-phenyl-2'-p-tolyl)-ethyl]propiolamide in 10 ml of dry THF is addeddropwise thereto while the temperature of the mixture is maintainedbelow -50°. The mixture is then stirred for 1 hr. at -20°. A solution of550 mg of diphenyl-methylchlorosilane in 3 ml of dry THF is addeddropwise, with stirring and the mixture stirred for 90 min (at -20°).

Aqueous saturated ammonium chloride is added to the reaction mixture,and the organic phase recovered, dried over anh. sodium sulfate, andconcentrated by evaporation in vacuo to obtain the crude product as anoil, which is refined by eluting through a silica gel column usingchloroform as eluate to yield the product of this step as an oil.

Step C: 4,4-diphenyl-4-sila-pentanoyl-1'-phenyl-2'-p-tolyl-ethylamide (aCompound I)

To a solution of 300 mg of4,4-diphenyl-4-sila-pent-2-ynoyl-(1'-phenyl-2'-p-tolyl)-ethylamide in 30ml of ethyl acetate in a hydrogenating apparatus, is added 50 mg ofplatinum oxide, and a pressure of 50 p.s.i. hydrogen is maintained for24 hours with shaking. The reaction mixture is then filtered, and thefiltrate concentrated (by evaporation in vacuo) to obtain the titleproduct as an oil.

EXAMPLE 24,4-Dimethyl-4-sila-pent-2-enoyl-(1'-phenyl-2'-p-tolyl)-ethylamide (aCompound II) ##STR29## Step A and B:4,4-dimethyl-sila-pent-2-ynol-(1'-phenyl-2'-p-tolyl)-ethylamide (aCompound III)

Repeating the procedure of Steps A and B of Example 1, but using inplace of the diphenylmethylchlorosilane used (in Step B) therein, anapproximately equivalent amount of trimethylchlorosilane, there isaccordingly obtained4,4-dimethyl-4-sila-pent-2-ynoyl-(1'-phenyl-2'-p-tolyl)-ethylamide (m.p.118°-120°).

Step C:4,4-dimethyl-4-sila-pent-2-enoyl-(1'-phenyl-2'-p-tolyl)-ethylamide

To a solution of 335 mg of4,4-dimethyl-4-sila-pent-2-ynoyl-(1'-phenyl-2'-p-tolyl)-ethylamide in 25ml of ethanol in a hydrogenating apparatus, is added 50 mg of 5%palladium on calcium carbonate. The mixture is placed under 1 at.pressure of hydrogen and shaken until an equivalent of hydrogen gas hadbeen taken up (about 45 min.). The reaction mixture is then filtered,and the filtrate concentrated (by evaporation in vacuo) to obtain thetitle product as an oil.

EXAMPLE 34,4-Dimethyl-4-sila-pentanoyl-(1'-phenyl-2'-p-tolyl)-ethylamide

Treating4,4-dimethyl-4-sila-pent-2-enoyl-(1'-phenyl-2'-p-tolyl)-ethylamide(obtained by Example 2) by the procedure of Step C of Example 1, thetitle product is obtained.

EXAMPLE 4

Following the procedure of Steps A and B of Example 1, but using inplace of the diphenylmethylchlorosilane used therein, an approximatelyequivalent amount of the following compounds V:

(a) dimethyl, n-propyl, chlorosilane;

(b) dimethyl, n-octyl, chlorosilane;

(c) t-butyl, dimethyl, chlorosilane;

(d) dimethyl, n-decyl, chlorosilane;

(e) dimethyl, phenyl, chlorosilane;

(f) diphenyl, methyl, bromosilane;

(g) benzyl, dimethyl, chlorosilane;

(h) dibenzyl, methyl chlorosilane;

(i) benzyl, methyl, phenyl, chlorosilane;

(j) dimethyl, p-tolyl-chlorosilane;

(k) diphenyl, n-octyl chlorosilane;

(l) triphenyl, chlorosilane;

(m) diphenyl, n-butyl chlorosilane;

(n) n-butyl-diethyl chlorosilane; or

(o) dimethyl-n-octadecyl, chlorosilane;

there is accordingly obtained the corresponding compound IIIrespectively:

(a) 4,4-dimethyl-4-sila-n-hept-2-ynoyl-(1'-phenyl-2-p-tolyl)-ethylamide;

(b)4,4-dimethyl-4-sila-n-dodec-2-ynoyl-(1'-phenyl-2-p-tolyl)-ethylamide;

(c)4-t-butyl-4-methyl-4-sila-pent-2-ynoyl-(1'-phenyl-2-p-tolyl)-ethylamide;

(d)4,4-dimethyl-4-sila-n-tetradec-2-ynoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;

(e)4-methyl-4-phenyl-4-sila-pent-2-ynoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;

(f) 4,4-diphenyl-4-sila-pent-2-ynoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;

(g)4,4-dimethyl-5-phenyl-4-sila-pent-2-ynoyl-(1'-phenyl-2'-p-tolyl)ethylamide(as an oil);

(h) 4,4-dibenzyl-4-sila-pent-2-ynoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;

(i)4-benzyl-4-phenyl-4-sila-pent-2-ynoyl-(1'-phenyl-(2'-p-tolyl)-ethylamide;

(j)4-methyl-4-p-tolyl-4-sila-pent-2-ynoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;

(k)4,4-diphenyl-4-sila-n-dodec-2-ynoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;

(l)4,4,4-triphenyl-4-sila-but-2-ynoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;

(m) 4,4-diphenyl-4-sila-n-oct-2-ynoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;

(n) 4,4-diethyl-4-sila-n-oct-2-ynoyl-(1'-phenyl-2'-p-tolyl)-ethylamide,and

(o) 4,4-dimethyl-sila-n-dodec-2-ynoyl(1'-phenyl-2'-p-tolyl)-ethylamide.

EXAMPLE 5

Repeating the procedure of step C of Example 2, but using in place ofthe 4,4-dimethyl-4-sila-pent-2-ynoyl-(1'-phenyl-2'-p-tolyl)-ethylamideused therein, an approximately equivalent amount of each of the products(a) to (o) of Example 4, there is accordingly obtained, respectively,the corresponding compounds II:

(a)4,4-dimethyl-4-sila-n-hept-2-enoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;

(b)4,4-dimethyl-4-sila-n-dodec-2-enoyl-(1'-phenyl-2-p-tolyl)-ethylamide;

(c)4-t-butyl-4-methyl-4-sila-pent-2-enoyl-(1'-phenyl-2-p-tolyl)-ethylamide*;

(d)4,4-dimethyl-4-sila-n-tetradec-2-enoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;

(e)4-methyl-4-phenyl-4-sila-pent-2-enoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;

(f) 4,4-diphenyl-4-sila-pent-2-enoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;

(g)4,4-dimethyl-5-phenyl-4-sila-pent-2-enoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;

(h) 4,4-dibenzyl-4-sila-pent-2-enoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;

(i)4-benzyl-4-phenyl-4-sila-pent-2-enoyl-(1'-phenyl-2'-tolyl)-ethylamide;

(j)4-methyl-4-p-tolyl-4-sila-pent-2-enoyl-(1'-phenyl-2'-p-tolyl)-ethylamide.

(k)4,4-diphenyl-4-sila-n-dodec-2-enoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;

(l) 4,4,4-triphenyl-4-sila-but-2-enoyl-(1'-phenyl-2'-p-tolyl)ethylamide;

(m) 4,4-diphenyl-4-sila-n-oct-2-enoyl-(1'-phenyl-2'-p-tolyl)ethylamide(as a wax);

(n) 4,4-diethyl-4-sila-n-oct-2-enoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;and

(o)4,4-dimethyl-4-sila-n-dodec-2-enoyl-(1'-phenyl-2'-p-tolyl)ethylamide.

EXAMPLE 6

Repeating the procedure of Step C of Example 1 using in place of the4,4-diphenyl-4-sila-pent-2-ynoyl-(1'-phenyl-2-p-tolyl)ethylamide usedtherein, an approximately equivalent amount of the products a to o ofExample 5 there is accordingly obtained respectively the correspondingcompounds Ia:

(a) 4,4-dimethyl-4-sila-n-heptanoyl-(1'-phenyl-2'-p-tolyl)-ethylamide,(as an oil);

(b) 4,4-dimethyl-4-sila-n-dodecanoyl-(1'-phenyl-2'-p-tolyl)-ethylamide,(as an oil);

(c)4-t-butyl-4-methyl-4-sila-pentanoyl-(1'-phenyl-2-p-tolyl)-ethylamide,(as an oil);

(d)4,4-dimethyl-4-sila-n-tetradecanoyl-(1'-phenyl-2'-p-tolyl)-ethylamide(m.p. 39°-42°);

(e)4-methyl-4-phenyl-4-sila-pentanoyl-(1'-phenyl-2'-p-tolyl)-ethylamide,(as a gum);

(f) 4,4-diphenyl-4-sila-pentanoyl-(1'-phenyl-2'-p-tolyl)-ethylamide, (asan oil);

(g)4,4-dimethyl-5-phenyl-4-sila-pentanoyl)-(1'-phenyl-2'-p-tolyl)ethylamide,(as an oil);

(h) 4,4-dibenzyl-4-sila-pentanoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;

(i)4-benzyl-4-phenyl-4-sila-pentanoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;

(j)4-methyl-4-p-tolyl-4-sila-pentanoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;

(k) 4,4-diphenyl-4-sila-n-dodecanoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;

(l) 4,4,4-triphenyl-4-sila-butanoyl-(1'-phenyl-2'-p-tolyl)-ethylamide;

(m) 4,4-diphenyl-4-sila-n-octanoyl-(1'-phenyl-2'-p-tolyl)-ethylamide (mp92°-97°);

(n) 4,4-diethyl-4-sila-n-octanoyl-(1'-phenyl-2'-p-tolyl)-ethylamide (asan oil); and

(o) 4,4-dimethyl-4-sila-n-dodecanoyl-(1'-phenyl-2'-p-tolyl)-ethylamide,(mp 64°-5°).

EXAMPLE 7 N-4,4-Dimethyl-4-sila-pentanoyl-benzylamide ##STR30##

Adapting the procedure of Example 2, but using in place of the(1'-phenyl-2'-p-tolyl)-ethylamine used therein, benzylamine, there isobtained from Steps A+B, N-4,4-dimethyl-4-sila-pent-2-ynoyl-benzylamide(m.p. 73°-76°), and from Step C,N-4,4-dimethyl-4-sila-pent-2-enoylbenzylamide (m.p. 68°-72°), which bytreatment by the procedure of Step C of Example 1, the title product isobtained (as an oil).

EXAMPLE 8

Repeating the procedure of Steps A and B of Example 1, but using inplace of the (1-phenyl-2-p-tolyl)-ethylamine used in Step A, therein, anapproximately equivalent amount of the following amines as compounds IX:

(a) 1-amino-indane;

(b) DL-tryptophan ethyl ester, hydrochloride;

(c) (d,l) α-methylbenzylamine; (racemate);

(d) 2-methylaniline; or

(e) 1-benzyl-2-phenylethylamine;

there is accordingly obtained, respectively (as compounds III):

(a) N-(4,4-diphenyl-4-sila-pent-2-ynoyl)-1-indanylamide;

(b) N-(4,4-diphenyl-4-sila-pent-2-ynoyl)-tryptophan, ethyl ester;

(c) N-(4,4-diphenyl-4-sila-pent-2-ynoyl)-α-methylbenzylamide; (as amixture of racemates, m.p. 34°);

(d) N-(4,4-diphenyl-4-sila-pent-2-ynoyl)-o-methylphenylamide; and

(e) N-(1'-benzyl-2'-phenyl)ethyl-4,4-diphenyl-4-silapenta-2-ynoylamide.

EXAMPLE 9

Repeating the procedure of Step C Example 2, above, but using in placeof the4,4-dimethyl-4-sila-pent-2-ynoyl-(1'-phenyl-2'-p-tolyl)-ethylamide usedtherein, an approximately equivalent amount of each of the products ofExample 8, there is accordingly obtained (as compounds II) there isaccordingly obtained, respectively:

(a) N-(4,4-diphenyl-4-sila-pent-2-enoyl)-1-indanylamide;

(b) N-(4,4-diphenyl-4-sila-pent-2-enoyl)-tryptophan, ethyl ester;

(c) N-(4,4-diphenyl-4-sila-pent-2-enoyl)-α-methylbenzylamide, (as aracemic mixture);

(d) N-(4,4-diphenyl-4-sila-pent-2-enoyl)-o-methylphenylamide; and

(e) N-(1'-benzyl-2'-phenyl)ethyl-4,4-diphenyl-4-silapenta-2-enoylamide.

EXAMPLE 10

Repeating the procedure of step C of Example 1, but using in place ofthe 4,4-diphenyl-4-sila-pent-2-ynoyl-(1-phenyl-2-p-tolyl)-ethylamideused therein, an approximately equivalent amount of the products ofExample 9, there is accordingly obtained, respectively:

(a) N-(4,4-diphenyl-4-sila-pentanoyl)-1-indanylamide;

(b) N-(4,4-diphenyl-4-sila-pentanoyl)-tryptophan, ethyl ester;

(c) N-(4,4-diphenyl-4-sila-pentanoyl)-α-methylbenzylamide, (as a racemicmixture);

(d) N-(4,4-diphenyl-4-sila-pentanoyl)-o-methylphenylamide; and

(e) N-(1'-benzyl-2'-phenyl)ethyl-4,4-diphenyl-4-silapentanoylamide*.

EXAMPLE 11

Repeating the procedures of Examples 2 and 3 but using in place of thetrimethylchlorosilane, used in Example 2, an approximately equivalentamount of dimethyl, n-decyl chlorosilane, and in place of the(1-phenyl-2-p-tolyl)ethylamine used in Example 2, an approximatelyequivalent amount of the following amines as Compounds IX:

(a) 1-amino-indane;

(b) DL-tryptophan ethyl ester, hydrochloride;

(c) (d,l) α-methylbenzyalmine; (racemate);

(d) 2-methylaniline;

(e) (1-benzyl-2-phenyl)ethylamine;

(f) (+)-α-methylbenzylamine;

(g) (+)-(1-phenyl-2-p-tolyl)ethylamine; or

(h) (-)-(1-phenyl-2-p-tolyl)ethylamine;

there is accordingly obtained, respectively:

(a) N-(4,4-dimethyl-4-sila-tetradecanoyl)-1-indanylamide;

(b) N-4,4-dimethyl-4-sila-tetradecanoyl-tryptophan, ethyl ester, (m.p.54°);

(c) N-(4,4-dimethyl-4-sila-tetradecanoyl)-α-methylbenzylamide, (as aracemate mixture);

(d) N-(4,4-dimethyl-4-sila-tetradecanoyl)-o-methylphenylamide;

(e) N-(1-benzyl-2-phenyl)ethyl-(4,4-dimethyl-4-silatetradecanoylamide(m.p. 70°-71°);

(f) (+)N-(4,4-dimethyl-4-sila-tetradecanoyl-1'-phenylethylamide (as anoil);

(g)(+)N-4,4-dimethyl-4-sila-tetradecanoyl-(1'-phenyl-2'-p-tolyl)ethylamide(as an oil); and

(h)(-)N-4,4-dimethyl-4-sila-tetradecanoyl-(1'-phenyl-2'-p-tolyl)ethylamide(as an oil).

EXAMPLE 124-(o-methoxyphenyl)-4-methyl-4-sila-pentanoyl-(1'-benzyl-2'-phenyl)ethylamide##STR31##

Following the procedure of Example 1, but in the first step, using inplace of the (1-phenyl-2-p-tolyl)-ethylamine, using an approximatelyequivalent amount of 1-benzyl 2-phenyl)-ethylamine; and in the secondstep using in place of the diphenyl-methylchlorosilane using anapproximately equivalent amount of theo-methoxyphenyl-dimethylchlorosilane, there is accordingly obtained thetitle product, m.p. 75°.

EXAMPLE 13 4,4-dimethyl-4-sila-4-dodecanoyl-α-methyl-benzylamide##STR32##

Following the procedure of Example 1, but in the first step using inplace of the (1-phenyl-2-p-tolyl)-ethylamine, using an approximatelyequivalent amount of α-methylbenzylamine; and in the second step usingin place of the diphenyl-methylchlorosilane using an approximatelyequivalent amount of dimethyl-n-octadecyl-chlorosilane there isaccordingly obtained the title product, m.p. 61°.

What is claimed is:
 1. A dianion of the formula ##STR33## in which R isof type (a) and aralkyl-type radical of the structure (a) ##STR34##wherein g is 0, 1 or 2;R^(a) is a hydrogen atom, halo having an atomicweight of from about 19 to 127, alkoxy having from 1 to 4 carbon atoms,or alkyl having from 1 to 4 carbon atoms, or trifluoromethyl; R^(b) is ahydrogen atom, alkyl having from 1 to 3 carbon atoms, alkoxy having from1 to 3 carbon atoms or halo having an atomic weight of from about 19 to36; and R^(c) is subtype (i) a hydrogen atom; subtype (ii), a radical ofthe structure (ii) ##STR35## in which p is 0, 1 or 2, and y is ahydrogen atom, halo having an atomic weight of from about 19 to 127,alkoxy having from 1 to 4 carbon atoms, or alkyl having from 1 to 4carbon atoms; and y' is a hydrogen atom, alkoxy having from 1 to 3carbon atoms, alkyl having from 1 to 3 carbon atoms, or halo having anatomic weight of from about 19 to 36; or subtype (iii) alkyl having from1 to 8 carbon atoms; R is of type (b) a phenyl-type radical of thestructure (b) ##STR36## in which R^(b) is as defined above, and R^(o) isa hydrogen atom, halo having an atomic weight of from about 19 to 127,alkoxy having from 1 to 4 carbon atoms, or alkyl having from 1 to 4carbon atoms; or R^(o) is a radical of the structure R^(f) : ##STR37##in which D is --CH₂ -- or --O--; f is 0 or 1; and W is a hydrogen atom,halo having an atomic weight of from about 19 to 80, alkoxy having from1 to 3 carbon atoms, or alkyl having from 1 to 3 carbon atoms; or R isof type (c) an indolyl radical of the structure: (c) ##STR38## whereinR^(b) is as defined above; R⁴ is hydrogen; an equivalent of a cationwhich results in the formation of a salt which is pharmaceuticallyacceptable; alkyl having from 1 to 8 carbon atoms; or benzyl; R⁵ is ahydrogen atom, alkyl having from 1 to 8 carbon atoms or benzyl; or R is(d) a benzocycloalkyl nucleus of the structure: (d) ##STR39## wherein yand y' are as defined above; and j is a whole integer of from 1 to 4;and each M is an equivalent of an alkali metal or a magnesium chlorideor bromide.
 2. A compound of claim 1 in which R is of type (a).
 3. Acompound of claim 1 in which R is of type (b).
 4. A compound of claim 1in which R is of type (c).
 5. A compound of claim 1 in which R is oftype (d).
 6. A compound of claim 1 in which M is lithium.
 7. A compoundof claim 1 in which R is (1'-phenyl-2'-p-tolyl)-ethyl.
 8. A compound ofclaim 1 in which M is an alkali metal.
 9. A process for the preparationof a compound of the formula: ##STR40## in which R is of type (a) anaralkyl-type radical of the structure: (a) ##STR41## wherein g is 0, 1or 2;R^(a) is a hydrogen atom, halo having an atomic weight of fromabout 19 to 127, alkoxy having from 1 to 4 carbon atoms, or alkyl havingfrom 1 to 4 carbon atoms, or trifluoromethyl; R^(b) is a hydrogen atom,alkyl having from 1 to 3 carbon atoms; alkoxy having from 1 to 3 carbonatoms or halo having an atomic weight of from about 19 to 36; and R^(c)is subtype (i) a hydrogen atom; subtype (ii), a radical of the structure(ii) ##STR42## in which p is 0, 1 or 2, and y is a hydrogen atom, halohaving an atomic weight of from about 19 to 127, alkoxy having from 1 to4 carbon atoms, or alkyl having from 1 to 4 carbon atoms; and y' is ahydrogen atom, alkoxy having from 1 to 3 carbon atoms, alkyl having from1 to 3 carbon atoms, or halo having an atomic weight of from about 19 to36; or subtype (iii) alkyl having from 1 to 8 carbon atoms; R is of type(b) a phenyl-type radical of the structure (b) ##STR43## in which R^(b)is as defined above, and R^(o) is a hydrogen atom, halo having an atomicweight of from about 19 to 127, alkoxy having from 1 to 4 carbon atoms,or alkyl having from 1 to 4 carbon atoms; or R^(o) is a radical of thestructure R^(f) : ##STR44## in which D is --CH₂ -- or --O--; f is 0 or1; and W is a hydrogen atom, halo having an atomic weight of from about19 to 80, alkoxy having from 1 to 3 carbon atoms, or alkyl having from 1to 3 carbon atoms; or R is of type (c) an indolyl radical of thestructure: (c) ##STR45## wherein R^(b) is as defined above; R⁴ is alkylhaving from 1 to 8 carbon atoms; or benzyl; and R⁵ is a hydrogen atom,alkyl having from 1 to 8 carbon atoms or benzyl; or R is (d) abenzocycloalkyl nucleus of the structure: (d) ##STR46## wherein y and y'are as defined above; and j is a whole integer of from 1 to 4; and M isan equivalent of an alkali metal or a magnesium chloride or bromide;which comprises reacting an amide of the formula: ##STR47## in which Ris as defined, with an M-contributing agent, in which M is as defined.10. A process of claim 9 in which M is an alkali metal.
 11. A process ofclaim 9 in which R is of type (a).
 12. A process of claim 9 in which theM-contributing agent is lithium diisopropylamide.
 13. A process for thepreparation of a compound of the formula: ##STR48## in which R is oftype (a) an aralkyl-type radical of the structure: (a) ##STR49## whereing is 0, 1 or 2;R^(a) is a hydrogen atom, halo having an atomic weight offrom about 19 to 127, alkoxy having from 1 to 4 carbon atoms, or alkylhaving from 1 to 4 carbon atoms, or trifluoromethyl; R^(b) is a hydrogenatom, alkyl having from 1 to 3 carbon atoms, alkoxy having from 1 to 3carbon atoms or halo having an atomic weight of from about 19 to 36; andR^(c) is subtype (i) a hydrogen atom; subtype (ii), a radical of thestructure (ii) ##STR50## in which p is 0, 1 or 2, and y is a hydrogenatom, halo having an atomic weight of from about 19 to 127, alkoxyhaving from 1 to 4 carbon atoms, or alkyl having from 1 to 4 carbonatoms; and y' is a hydrogen atom, alkoxy having from 1 to 3 carbonatoms, alkyl having from 1 to 3 carbon atoms, or halo having an atomicweight of from about 19 to 36; or subtype (iii) alkyl having from 1 to 8carbon atoms; R is of type (b) a phenyl-type radical of the structure(b) ##STR51## in which R^(b) is as defined above, and R^(o) is ahydrogen atom, halo having an atomic weight of from about 19 to 127,alkoxy having from 1 to 4 carbon atoms, or alkyl having from 1 to 4carbon atoms; or R^(o) is a radical of the structure R^(f) : ##STR52##in which D is --CH₂ -- or --O--; f is 0 or 1; and W is a hydrogen atom,halo having an atomic weight of from about 19 to 80, alkoxy having from1 to 3 carbon atoms, or alkyl having from 1 to 3 carbon atoms; or R isof type (c) an indolyl radical of the structure: (c) ##STR53## whereinR^(b) is as defined above; R⁴ is alkyl having from 1 to 8 carbon atoms;or benzyl; R⁵ is a hydrogen atom, alkyl having from 1 to 8 carbon atomsor benzyl; or R is (d) a benzocycloalkyl nucleus of the structure: (d)##STR54## wherein y and y' are as defined above; and j is a wholeinteger of from 1 to 4; and each of R¹, R² and R³ is, independently, (a)alkyl having from 1 to 22 carbon atoms; or (b) of the formula ##STR55##in which m is 0, 1 or 2, and each of R' and R" is independently ahydrogen atom, alkyl having from 1 to 3 carbon atoms, alkoxy having from1 to 3 carbon atoms, or halo having an atomic weight of from about 19 to127; which comprises the steps of (a) reacting a dianion of a compoundof the formula: ##STR56## in which R as defined, and M is an equivalentof an alkali metal or a magnesium chloride or bromide; with atri-substituted-halo silane of the formula: ##STR57## in which R¹, R²and R³ are as defined, and Z is halo having an atomic weight of fromabout 19 to 127, to form an adduct; and (b) hydrolyzing said adduct. 14.A process of claim 13 in which R² is methyl and each of R² and R³ isphenyl.
 15. A process of claim 13 in which R is(1'-phenyl-2'-p-tolyl)-ethyl.
 16. A process of claim 13 in which M islithium.
 17. A process of claim 13 in which M is an alkali metal.
 18. Aprocess of claim 13 in which R is of type (a).
 19. A process of claim 13in which two of R¹, R² and R³ are the same.
 20. A process of claim 13 inwhich Z is chloro.